U.S. Pat. No. 4,395,399 to Ovchinnikov et al. disclosed glycopeptides of formula I
wherein Y′ is a residue of an aminoacid or linear peptide of 2 to 5 amino acid residues. These glycopeptides are prepared by coupling unblocked muramyl-containing N-acetylamino-sugars of formula II
with blocked aminoacids or peptides. The disaccharide acid of formula II is obtained from large-scale fermentation of the bacterium Micrococcus lysodeicticus. The peptide portion is produced by conventional synthetic methods.
Compounds of formula I (hereinafter referred to as “Ovchinnikov glycopeptides”), particularly N-acetylglucosaminyl-N-acetylmuramyl-L-alanyl-D-isoglutamine (GMDP) and N-acetylglucosaminyl-N-acetylmuramyl-L-alanyl-D-glutamic acid (GMDP-A), are orally-active immunomodulators for use in a number of indications. (see, e.g., Ivanov, V. T., et al., Immunologiya No. 2, 4–5 (1996); Adrianova, I. E., et al., Radiobiologiia 32, 566–70 (1992); Palache, A. M., et al., Vaccine 14, 1327–30 (1996); and Khaitov, R. M., et al., “Immunotheraphy of Infections,” Ed. Masihi, N., 205–211 (Marcel Dekker, Inc., 1994)). For example, compounds of formula I possess adjuvant activity. Adjuvants are compounds causing non-specific stimulation of the immune system in human beings and animals, resulting in an increased production of antibodies and enhancement of protective reaction of the organism against infection. Adjuvants are used in medicine for the manufacture of vaccines and sera. In addition, U.S. Pat. No. 5,506,204 to R. Aston discloses the use of GMDP and GMDP-A for treatment of septic shock.
The semi-synthetic approach for preparing glycopeptides of formula I described above is utilized because the disaccharide core, N-acetyl-(2-deoxy-2-aminoglucopyranosyl)-β-[1,4]-N-acetylmuramic acid, is one of the most difficult glucopyranosyl-glucopyranose disaccharides to synthesize. For example, the order of glucopyranose hydroxyl acceptor reactivity toward glycosyl cation donors, independent of donor source, is water>>ethanol>C(6)OH>C(2)OH>C(3)OH> the required C(4)OH. In addition, 2-deoxy-2-acylaminoglucopyranose C(4)OH acceptors are deactivated electronically relative to glucose itself. Muramic acid derivatives, in particular, suffer still further acceptor reactivity disadvantage due to steric crowding around the C(4) oxygen. Formation of the desired β-[1,4]-glycosidic bond requires a 2-deoxy-2-aminoglucopyranose glycosyl cation donor with a nitrogen substituent that will favor equatorial approach of the very modestly nucleophilic C(4)OH of a muramic acid derivative.
Several approaches to this formidable glycosidation problem have been documented. (see, e.g., Mercer, C., et al., Tetrahedron Lett. 13, 1029 (1973); Durette, P. L., et al., Carbohydr. Res., 77, C1 (1979); Kusumoto, D., et al., Bull. Chem. Soc. Jpn., 59, 1411 (1986); Kusumoto, D., et al., Bull. Chem. Soc. Jpn., 59, 1419 (1986); Farkas, J., et al., Carbohydr. Res., 163, 63 (1987); Kinzy, W., et al., Liebigs Ann. Chem., 407 (1987) ; Termin, A., et al., Liebigs Ann. Chem., 789 (1989); Ledvina, M., et al., Collect. Czech. Chem. Commun., 54, 2784 (1989) and Termin, A., et al., Liebigs Ann. Chem., 527 (1992). However, none of these approaches provides a process for preparing the disaccharide in sufficient amounts to be useful as an intermediate in the preparation of glycopeptides of formula I.